1. Field of the Invention
The present invention relates to novel sulfated tannins and their salts as well as an antiviral agent, in particular, that for retrovirus and a reverse transcriptase inhibitor.
2. Description of the Prior Art
Regarding viral infectious diseases, there has been desired to develop antiviral agents for use in their routine treatment. However, clinically effective ones have not yet been developed and hence the treatment thereof should in general rely on the symptomatic treatment. Recently, the development and investigation of anti-viral agents for herpesvirus, those for AIDS (acquired immune deficiency syndrome) virus or the like have increased. Under such circumstances, the inventors of this invention have conducted studies to develop antiviral agents effective against AIDS virus and herpesvirus as well as other virus.
AIDS was reported for the first time in the United States in 1981 (see Gottlieb, M. S. et al., N. Engl. J. Med., 1981, 305, p. 1425; and Siegal, F. P. et al., N. Engl. J. Med., 1981, 305, p. 1439). Thereafter, the virus HIV (human immunodeficiency virus) which causes AIDS was identified in 1983 by Montagnier (France) (Barre-Sinoussi, F. et al., Science, 1983,220, p. 868) and then by Gallo (American) (Popovic, M. et al., Science, 1984, 224, p. 497).
It has been found, as a result of exploration of substances exhibiting infection-inhibitory effect, that azidothymidine (AZT) which is an analogue of nucleic acid (see Hiroaki Mitsuya et al., Proc. Natl. Acad. Sci. USA, 1985, 82, p. 7096; Hideki Nakajima et al., Antimicrob. Agents Chemother., 1986, 30, p. 933) and various kinds of dideoxynucleosides (see Hiroaki Mitsuya et al., Proc. Natl. Acad. Sci. USA, 1986, 83, p. 1911; Y. Hamamoto et al., Antimicrob. Agents Chemother., 1987, 31, p. 907) exhibit effect of apothanasia on the basis of in vivo studies and have been approved as an agent for treating AIDS.
However, patients suffering from AIDS must take AZT for a long period of time and thus various problems such as side-effects are still present.
In addition, Yamamoto et al. reported that the formation of multinucleated giant cells (Syncytium) could not be suppressed by simply employing AZT in a giant cell formation inhibitory experiment by co-cultivation of MOLT-4 and MOLT-4/HIV cells (see Hideki Nakashima, et al., Virology, 1987, 159, p. 169). It is thought that the formation of such giant cells plays an important role in the crisis of AIDS.
On the other hand, Nakashima and Yamamoto et al. have found that natural polysaccharides such as sulfated polysaccharides present in seaweeds and lentinan sulfate as well as other sulfated derivatives of polysaccharides (synthetic sulfated polysaccharides) have inhibitory effect on HIV infection (see Hideki Nakashima et al., Gann, 1987, 78, p. 1164).
Moreover, it is known that a certain kinds of polyphenols which are not sulfated show herpesvirus inhibitory effect and HIV inhibitory effect (Journal of Natural Products, 1989, vol. 52, No. 4, pp. 762-768).
For instance, there have been known herpesvirus inhibitory effect of (-)-epigallocatechin, procyanidine B2 3,3'-di-O-gallate and ratamenine belonging to condensed tannins (see Genichiro Nonaka et al., Collected Resume of 34th General Meeting of Japan Virus Society, 1986, Oct., p. 214) and HIV inhibitory effect of Agrimoniin, Coriariin A and Oanothein B belonging to hydrolyzable tannin (see Miyuki Asanaka, et al., Collected Resume of 1st Scientific Meeting of the Society for the Research on AIDS, 1987, Dec., p. 61). Further, it has been recently reported that a polyphenol type compound containing polysaccharides obtained by extracting pinecones of GOYO pine with hot water shows inhibitory effects on influenza virus, herpesvirus, hepatitis B virus and HIV (morning edition of the YOMIURI, Dec. 18, 1988).